Rational design of novel I1-imidazoline receptor agonists

For several years our interest has been focused on the characterization of the imidazoline binding sites (IBS) described for the first time by Bousquet and coworkers in 1984. Findings from different laboratories have shown that they are widely distributed in different tissues, including both central and peripheral nervous systems, of various species, including man. Numerous binding and functional studies have confirmed their existence and shown their heterogeneity. I1-IBS, also called I1-imidazoline receptors (I1Rs), represent targets for antihypertensive imidazole like molecules, such as clonidine, rilmenidine and moxonidine. The hypotensive activity of these compounds was shown to be mediated by both central alpha2-adrenergic receptors (alpha2-ARs) and I1Rs. The involvement of I1Rs is particularly critical for rilmenidine and moxonidine that reveal significant selectivity for the I1Rs, although they bind with good affinity to both receptors. Moreover, compared to clonidine, the typical side effects of alpha2-AR activation induced by these drugs are reduced. Recently, we have observed that very interesting modulation of receptor interactions was obtained by introduction of a phenyl group into the ortho position of the aromatic ring of the highly selective I1R antagonist 1 (I1/I2 = 186; I1/alpha2 = 708). In fact, 2 retained good I1R selectivity, and, interestingly, when injected intracisternally (ic) in pentobarbital anaesthetized normotensive rats, decreased mean arterial blood pressure (MAP) and heart rate (HR) significantly in a dose dependent manner. In addition, 2 was inactive on alpha 2-ARs [1]. Therefore, to confirm the interesting biological profile modulation from antagonist to agonist behavior, as verified for 2, and to discover novel I1R ligands possibly endowed with desirable antihypertensive activity, we introduced some bioisosteres of the phenyl group or aliphatic or halogen moieties into the ortho position of the aromatic ring of 1 (compounds 3-8). To evaluate their cardiovascular effect the derivatives were injected intravenously (iv) in hypertensive rats at a dose of 10 mg/kg. The significant antihypertensive property and the lack of alpha2-AR activation, whatever the subtypes showed by the tested compounds 3 and 6 allow the above observation to be confirmed and strengthen the validity of our design. [1] Gentili, F.; Bousquet, P.; Carrieri, A.; Feldman, J.; Ghelfi, F.; Giannella, M.; Piergentili, A.; Quaglia, W.; Vesprini, C.; Pigini M. Rational design of the new antihypertensive I1-receptor ligand 2-(2-biphenyl-2-yl-1-methyl-ethyl)-4,5-dihydro-1H-imidazole. Lett. Drug Des. Discov. 2005; 2, 571-578, and references therein.